Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. (DIAN-TU)

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The purpose of this study is to assess the safety, tolerability, biomarker and cognitive efficacy of investigational products in subjects who are known to have an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive impairment and improves disease-related biomarkers.

This study also offers an observational component collecting cognitive assessment data until the availability of an enrolling drug treatment group, referred to as cognitive run-in (CRI).

The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with dominantly inherited Alzheimer's disease have very high penetrance (near 100%). This study will target individuals who are either known to have a disease-causing mutation or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and with each mutation (Ryman, Acosta-Baena et al. 2014), an age at onset is determined for each affected parent or mutation. This study will enroll subjects who are either asymptomatic and are within a specific window of time of expected age at onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease.

The ability to identify individuals destined to develop Alzheimer's disease (AD) within the next 10-15 years with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies while individuals are asymptomatic and/or very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Many of the subjects in this study will not yet have any cognitive symptoms of AD; they will be "asymptomatic" carriers of mutations that cause dominantly inherited Alzheimer's disease and would be expected to perform normally on standard cognitive and functional testing. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation or not, some of the at-risk individuals enrolled in this study will not have the disease causing mutations; they will be "mutation negative". It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be pressured into genetic testing to learn their genetic status in order to be eligible for the trial). These mutation negative individuals will be assigned to the placebo group; and will not be included in the primary efficacy or futility analyses. Subjects and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be double blinded for placebo and for mutation status, except for mutation positive subjects who are aware of their genetic status. There may be exceptional circumstances when required by local regulation or health authorities where enrollment may be restricted to mutation carriers only but such mandates will be thoroughly documented and agreed upon by the governing regulatory agency and sponsor. Several different therapies (each referred to as a study drug arm) will be tested in order to increase the likelihood that an effective treatment will be discovered. The compounds are selected for this trial based on mechanism of action and available data on efficacy and safety profile.

The study design includes a pooled placebo group shared by all study drug arms. Mutation positive subjects will be assigned to a study drug arm and subsequently randomized within that arm in an overall 3:1 ratio to active drug:placebo. Mutation negative subjects will all receive placebo treatment. Importantly, subjects and study staff will not be blinded as to which study drug arm (gantenerumab or solanezumab) each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo. Biomarker data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. The primary cognitive endpoint will be the same for all study drug arms. This study is an adaptive platform based study. Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study drug engages its biological targets. This biomarker approach is particularly important in this study as most study subjects will be cognitively normal at baseline and most will remain cognitively normal during the first 2 years of the study. The cognitive composite is designed to assess subtle cognitive changes that may be detectable before the onset of dementia. The cognitive disease progression model (CDPM) endpoint design will allow for detection of these subtle cognitive changes.

A cognitive run-in (CRI) period may open for recruitment if no study drug arm is available for immediate enrollment, or if a treatment arm is stopped prior to the planned completion (e.g., at biomarker interim, drug toxicity). The CRI period will enhance study enrollment by identifying eligible subjects and engaging them with the cognitive process, and can reduce fluctuations in practice effects by allowing subjects to become accustomed to the testing process.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years to 80 Years (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

Between 18-80 years of age

Individuals who know they have an Alzheimer's disease-causing mutation or are unaware of their genetic status and have an autosomal dominant Alzheimer's disease (ADAD) mutation in their family.

Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset for treatment arms. For Cognitive Run-In (CRI): includes participants who are younger than 15 years prior to the expected age of cognitive symptom onset, in addition to those 15 years younger and no more than 10 years older than expected or actual age of cognitive symptom onset.

For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide).

Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.

Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion.

Exclusion Criteria:

History or presence of brain MRI scans indicative of any other significant abnormality